Reactor for coating particles in stationary chamber with rotating paddles

ABSTRACT

A reactor for coating particles includes a stationary vacuum chamber to hold a bed of particles to be coated, a vacuum port in an upper portion of the chamber, a chemical delivery system configured to inject a reactant or precursor gas into a lower portion of the chamber, a paddle assembly, and a motor to rotate a drive shaft of the paddle assembly. The lower portion of the chamber forms a half-cylinder. The paddle assembly includes a rotatable drive shaft extending through the chamber along the axial axis of the half cylinder, and a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft by the motor orbits the plurality of paddles about the drive shaft.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/855,860, filed on Apr. 22, 2020, which claims priority to U.S.Application Ser. No. 62/838,233, filed on Apr. 24, 2019, the disclosureof which is incorporated by reference.

TECHNICAL FIELD

This disclosure pertains coating particles, e.g., particles that includeactive pharmaceutical ingredients, with thin organic and inorganicfilms.

BACKGROUND

It is of great interest to the pharmaceutical industry to developimproved formulations of active pharmaceutical ingredients (API).Formulation can influence the stability and bioavailability of the APIas well as other characteristics. Formulation can also influence variousaspects of drug product (DP) manufacture, for example, ease and safetyof the manufacturing process.

Numerous techniques for encapsulating or coating API have beendeveloped. Some existing techniques for the coating of API include spraycoating, plasma polymerization, hot wire chemical vapor deposition(CVD), and rotary reactors. Spray coating is an industrially scalabletechnique that has been widely adopted by the pharmaceutical industry.However, coating non-uniformities (both within particle and fromparticle to particle) prevent the use of these techniques for improvingthe delivery profile or stability of active pharmaceutical ingredients(APIs). Particle agglomeration during spray coating also causessignificant challenges. Meanwhile, techniques such as plasmapolymerization are difficult to scale, applicable only to certainprecursor chemistries, and can result in the degradation of sensitiveAPIs. Existing hot-wire CVD processes utilizing hot wire radical sourcesinside the reaction vessel are poorly scalable and are not suitable forthermally sensitive APIs. Rotary reactors include atomic layerdeposition (ALD) and initiated CVD (iCVD) reactors. However, ALDreactors are suitable for inorganic coatings and not for organic polymercoatings, and existing iCVD designs do not adequately prevent APIdegradation and are not scalable for high volume manufacturing. Othertechniques include polymer mesh coating, pan coating, aerosolizedcoating, and fluidized bed reactor coating.

SUMMARY

In one aspect, a reactor for coating particles includes a stationaryvacuum chamber to hold a bed of particles to be coated, a vacuum port inan upper portion of the chamber, a chemical delivery system configuredto inject a reactant or precursor gas into a lower portion of thechamber, a paddle assembly, and a motor to rotate a drive shaft of thepaddle assembly. The lower portion of the chamber forms a half-cylinder.The paddle assembly includes a rotatable drive shaft extending throughthe chamber along the axial axis of the half cylinder, and a pluralityof paddles extending radially from the drive shaft such that rotation ofthe drive shaft by the motor orbits the plurality of paddles about thedrive shaft.

Implementations may include one or more of the following features.

The plurality of paddles may be configured to sweep along an entirety ofa length of the chamber. Outer edges of the paddles may be separatedfrom an inner surface of the lower portion of the chamber wall by a gap.The gap may be 1-3 mm.

The plurality of paddles may include a first plurality of outer paddlesat a first radial distance from the drive shaft and a first plurality ofinner paddles at a second radial distance from the drive shaft. Thesecond radial distance may be smaller than the first radial distance.The first plurality of outer paddles may be oriented at a first obliqueangle so as to drive particles in a first direction along the axialaxis, and the first plurality of inner paddles may be oriented at asecond oblique angle so as to drive particles in a second directionalong the axial axis opposite to the first direction. The second obliqueangle may be equal in magnitude and opposite in sign to the firstoblique angle.

The plurality of paddles may include a second plurality of outer paddlesat a third radial distance from the drive shaft and a second pluralityof inner paddles at a fourth radial distance from the drive shaft. Thefourth radial distance may be smaller than the third radial distance.The third radial distance may equal the first radial distance and thefourth radial distance may equal the second radial distance.

The second plurality of outer paddles may be oriented at a third obliqueangle so as to drive particles in the second direction and the secondplurality of inner paddles are oriented at a fourth oblique angle so asto drive particles in the first direction. The third oblique angle mayequal the second oblique angle, and the fourth oblique angle may equalthe first oblique angle. The first plurality of outer paddles and thefirst plurality of inner paddles may be positioned on a first side of adividing plane through the chamber normal to the axial axis, and thesecond plurality of outer paddles and the second plurality of innerpaddles may be positioned on an opposite second side of the dividingplane. A port to deliver particles to or receive particles from thechamber may be positioned at the dividing plane. The first plurality ofouter paddles and the second plurality of outer paddles may be orientedso as to drive particles toward the port, and the first plurality ofinner paddles and the second plurality of inner paddles may be orientedso as to drive particles away from the port.

The plurality of paddles may include paddles spaced uniformly along thedrive shaft. The plurality of paddles may include a plurality of groupsof paddles, and each group of paddles may be positioned in a commonplane normal to the drive shaft.

In another aspect, a method of coating particles includes dispensingparticles into a vacuum chamber to fill at least a lower portion of thechamber that forms a half-cylinder, evacuating the chamber through avacuum port in an upper portion of the chamber, rotating a paddleassembly such that a plurality of paddles orbit a drive shaft, andinjecting a reactant or precursor gas into the lower portion of thechamber as the paddle assembly rotates.

Implementations may include one or more of the following features.

The particles may be coated by atomic layer deposition or molecularlayer deposition. The particles may have a core containing a drug.

Implementations may include, but are not limited to, one or more of thefollowing possible advantages. Particles, e.g., API particles, can becoated with in a high volume manufacturing process, thereby providinglower cost of manufacturing and reduced drug product prices. Particlescan be coated with a thin layers, thus providing a drug product with anadvantageous volume fraction of API. In addition, the process can resultin layer(s) encapsulating the API that are uniform within a particle andfrom particle-to-particle, providing more consistent properties to thedrug formulations.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic front view of a reactor for ALD and/or CVD coatingof particles, e.g., drugs, that includes a stationary drum.

FIG. 2 is a schematic side view of the reactor of FIG. 1 . FIG. 2 can betaken along line 2-2 in FIG. 1 .

FIG. 3A is a schematic side view of a paddle assembly.

FIG. 3B is a front side view of the paddle assembly of FIG. 3A. FIG. 3Bcan be taken along line 3B-3B in FIG. 3A.

FIG. 3C is a schematic side view of another implementation of a paddleassembly.

FIG. 3D is a front side view of the paddle assembly of FIG. 3C. FIG. 3Dcan be taken along line 3D-3D in FIG. 3C.

FIG. 4 is a schematic perspective view of a paddle.

FIG. 5 is a schematic side view of a group of paddles from a paddleassembly.

FIG. 6A is a schematic side view of another implementation of a group ofpaddles from a paddle assembly.

FIG. 6B is a schematic side view of yet another implementation of agroup of paddles from a paddle assembly.

FIG. 7 is a schematic side view of a paddle from the group of paddles inFIG. 5 or 6 . FIG. 7 can be taken along line 7-7 in FIG. 5 .

FIG. 8 is a schematic side view of gas injection ports. FIG. 8 can betaken along line 8-8 in FIG. 1 .

FIG. 9 is a schematic top view the gas injection ports of FIG. 8 .

FIG. 10 is a schematic perspective view, partially cross-sectional,showing a gas injection port.

Like reference numbers and designations in the various drawings indicatelike elements.

DETAILED DESCRIPTION

There are various methods for encapsulating API particles. In manycases, these methods result in a coating that is relatively thick. Whilesuch coatings can impart desirable properties, the high ratio of coatingto API can make it difficult to create a drug product in which thevolume fraction of API is as high as desired. In addition, the coatingencapsulating the API can be non-uniform, making it difficult to provideformulations with consistent properties. Furthermore, coating techniquesthat can provide satisfactory consistency have not be scalable forindustrial manufacturing.

An approach that may address these issues is to use a stationary “drum”in which particles are agitated by rotating paddles, and process gas isinjected into the drum through the drum sidewall. This can force theprocess gas to percolate through the particle bed, which can improveuniformity of coating across the particles.

Drug

The term “drug,” in its broadest sense includes all small molecule(e.g., non-biologic) APIs. The drug could be selected from the groupconsisting of an analgesic, an anesthetic, an anti-inflammatory agent,an anthelmintic, an anti-arrhythmic agent, an antiasthma agent, anantibiotic, an anticancer agent, an anticoagulant, an antidepressant, anantidiabetic agent, an antiepileptic, an antihistamine, an antitussive,an antihypertensive agent, an antimuscarinic agent, an antimycobacterialagent, an antineoplastic agent, an antioxidant agent, an antipyretic, animmunosuppressant, an immunostimulant, an antithyroid agent, anantiviral agent, an anxiolytic sedative, a hypnotic, a neuroleptic, anastringent, a bacteriostatic agent, a beta-adrenoceptor blocking agent,a blood product, a blood substitute, a bronchodilator, a bufferingagent, a cardiac inotropic agent, a chemotherapeutic, a contrast media,a corticosteroid, a cough suppressant, an expectorant, a mucolytic, adiuretic, a dopaminergic, an antiparkinsonian agent, a free radicalscavenging agent, a growth factor, a haemostatic, an immunologicalagent, a lipid regulating agent, a muscle relaxant, aparasympathomimetic, a parathyroid calcitonin, a biphosphonate, aprostaglandin, a radio-pharmaceutical, a hormone, a sex hormone, ananti-allergic agent, an appetite stimulant, an anoretic, a steroid, asympathomimetic, a thyroid agent, a vaccine, a vasodilator and axanthine.

Exemplary types of small molecule drugs include, but are not limited to,acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasonepropionate, salmeterol, pazopanib HCl, palbociclib, and amoxicillinpotassium clavulanate.

Pharmaceutically Acceptable Excipients, Diluents, and Carriers

Pharmaceutically acceptable excipients include, but are not limited to:

-   -   (1) surfactants and polymers including: polyethylene glycol        (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate,        polyvinylalcohol, crospovidone,        polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose        derivatives, hydroxypropylmethyl cellulose, hydroxypropyl        cellulose, carboxymethylethyl cellulose, hydroxypropyllmethyl        cellulose phthalate, polyacrylates and polymethacrylates, urea,        sugars, polyols, carbomer and their polymers, emulsifiers, sugar        gum, starch, organic acids and their salts, vinyl pyrrolidone        and vinyl acetate;    -   (2) binding agents such as cellulose, cross-linked        polyvinylpyrrolidone, microcrystalline cellulose;    -   (3) filling agents such as lactose monohydrate, lactose        anhydrous, microcrystalline cellulose and various starches;    -   (4) lubricating agents such as agents that act on the        flowability of a powder to be compressed, including colloidal        silicon dioxide, talc, stearic acid, magnesium stearate, calcium        stearate, silica gel;    -   (5) sweeteners such as any natural or artificial sweetener        including sucrose, xylitol, sodium saccharin, cyclamate,        aspartame, and acesulfame K;    -   (6) flavoring agents;    -   (7) preservatives such as potassium sorbate, methylparaben,        propylparaben, benzoic acid and its salts, other esters of        parahydroxybenzoic acid such as butylparaben, alcohols such as        ethyl or benzyl alcohol, phenolic chemicals such as phenol, or        quarternary compounds such as benzalkonium chloride;    -   (8) buffers;    -   (9) Diluents such as pharmaceutically acceptable inert fillers,        such as microcrystalline cellulose, lactose, dibasic calcium        phosphate, saccharides, and/or mixtures of any of the foregoing;    -   (10) wetting agents such as corn starch, potato starch, maize        starch, and modified starches, and mixtures thereof;    -   (11) disintegrants; such as croscarmellose sodium, crospovidone,        sodium starch glycolate; and    -   (12) effervescent agents such as effervescent couples such as an        organic acid (e.g., citric, tartaric, malic, fumaric, adipic,        succinic, and alginic acids and anhydrides and acid salts), or a        carbonate (e.g., sodium carbonate, potassium carbonate,        magnesium carbonate, sodium glycine carbonate, L-lysine        carbonate, and arginine carbonate) or bicarbonate (e.g. sodium        bicarbonate or potassium bicarbonate)

Metal Oxide Material

The term “metal oxide material,” in its broadest sense includes allmaterials formed from the reaction of elements considered metals withoxygen-based oxidants. Exemplary metal oxide materials include, but arenot limited to, aluminum oxide, titanium dioxide, iron oxide, galliumoxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide,tantalum oxide, lanthanum oxide, and zirconium dioxide. Exemplaryoxidants include, but are not limited to, water, ozone, and inorganicperoxide. The term “oxide material” includes metal oxide materials aswell as oxides of other materials, e.g., silicon dioxide.

Atomic Layer Deposition (ALD)

Atomic layer deposition is a thin film deposition technique in which thesequential addition of self-limiting monolayers of an element orcompound allows deposition of a film with thickness and uniformitycontrolled to the level of an atomic or molecular monolayer.Self-limited means that only a single atomic layer is formed at a time,and a subsequent process step is required to regenerate the surface andallow further deposition.

Molecular Layer Deposition (MLD)

Molecular layer deposition is analogous to atomic layer deposition butusing organic precursors and forming organic thin films. During atypical MLD process two homo-bifunctional precursors are used. A firstprecursor is introduced into a chamber. The molecules of the firstprecursor react with reactive groups on the substrate surface via thecorresponding linking chemistry to add a molecular layer of the firstprecursor on the substrate surface with new reactive sites. Afterpurging, a second precursor is introduced and the molecules of thesecond precursor react with the new reactive sites provided by the firstprecursor generating a molecular layer of the first precursor linked tothe second precursor. This is followed by another purge cycle.

Reactor System

FIGS. 1-2 illustrate a reactor system 100 for coating particles with athin-film coating. The reactor system 100 can perform the coating usingALD and/or MLD coating conditions. The reactor system 100 permits adeposition process (ALD or MLD), to be performed at higher (above 50°C., e.g., 50-100° C.) or lower processing temperature, e.g., below 50°C., e.g., at or below 35° C. For example, the reactor system 100 canform thin-film oxides on the particles primarily by ALD at temperaturesof 22-35° C., e.g., 25-35° C., 25-30° C., or 30-35° C. In general, theparticles can remain or be maintained at such temperatures. This can beachieved by having the reactant gases and/or the interior surfaces ofthe reactor chamber remain or be maintained at such temperatures.

The reactor system 100 includes a stationary vacuum chamber 110 thatencloses a paddle assembly 150.

The vacuum chamber 110 is enclosed by chamber walls 112. A lower portion110 a of the chamber 110 forms a half-cylinder with a semicircularcross-section (as viewed along the central axis of the half-cylinder).The cross-section (again, as viewed along the central axis of thehalf-cylinder) of the upper portion 110 b can be uniform along thelength of the chamber 110 (the length is along the central axis of thehalf-cylinder). This can help ensure uniform gas flow along the lengthof the chamber. If gas flow is sufficiently uniform, the cross sectioncan be non-uniform, e.g., narrowing toward the top when viewedhorizontal but perpendicular to the central axis of the half-cylinder)to reduce the volume of the chamber 110.

The cross-section of the upper portion 110 b can otherwise be selectedto conserve space in the fabrication facility while still enclosing thepaddle assembly 150. For example, the upper portion 110 b of the chamber110 can be a rectangular solid (see FIG. 6A), a half-cylinder with asemicircular cross-section, or other appropriate shape that does notblock rotation of the paddle assembly 150. In some implementations, theupper portion 110 b of the chamber has a lower section 110 c that isadjacent the lower portion 110 a and that has vertical side walls, e.g.,a rectangular solid volume. An upper section 110 d that extends betweenthe lower section 110 c and a ceiling 112 a of the chamber 110 can havea cross-section (again, as viewed along the central axis of thehalf-cylinder) that is triangular or trapezoidal.

In some implementations, e.g., as shown in FIG. 6B (but which could becombined with other paddle assemblies), the curved portion of thechamber wall along the lower section 110 c of the upper chamber 110 b.An upper section 110 d that extends between the lower section 110 c anda ceiling 112 a of the chamber 110 can provide a volume for a vacuumport 132 and/or a powder delivery port 116. This configuration can avoidpowder build up, e.g., caused by the paddle assembly throwing thepowder, along a portion of the side wall 12 that is out of reach of thepaddles 154.

The chamber walls 110 can be a material, e.g., stainless steel, that isinert to the deposition process, and/or the interior surfaces of thechamber walls 110 can be coated with a material that is inert to thedeposition process. In some implementations, a viewing port 114 oftransparent material, e.g., quartz, can be formed through the chamberwall 112 to permit an operator to view an interior of the chamber 110.

In operation, the chamber 110 is partially filled by particles, e.g.,API-containing particles, that provide a particle bed 10. For superiorthroughput, the particle bed 10 fills at least the lower portion 110 aof the chamber, e.g., the top surface 12 of the particle bed 10 is at orabove the lower portion 110 a (indicated at A). On the other hand, thetop surface 12 of the particle bed 10 should be below the top (indicatedat B) of the paddle assembly 150 to avoid poor mixing of the particlebed. The chamber walls 112 can include one or more sealable ports 116 topermit the particles to be placed into and removed from the chamber 110.

The chamber 110 is coupled to a vacuum source 130. The port 132 throughthe chamber wall 112 to connect the vacuum source 130 to the chamber canbe located in the upper portion 110 b of the chamber 110. In particular,the port 132 can be located above the expected position of the topsurface 12 of the particle bed, e.g., above the top (indicated at B) ofthe paddle assembly 150, e.g., in the chamber ceiling.

The vacuum source 130 can be an industrial vacuum pump sufficient toestablish pressures less than 1 Torr, e.g., 1 to 100 mTorr, e.g., 50mTorr. The vacuum source 130 permits the chamber 110 to be maintained ata desired pressure, and permits removal of reaction byproducts andunreacted process gases.

The port 132 can be covered by a filter 134 to prevent particles throwninto the gas stream by the paddle assembly from escaping the reactorchamber 110. In addition, the system can include a filter cleaner toclear particles off the filter 134. As one example, the filter cleanercan be a mechanical knocker to strike the filter; this make shakeparticles off the filter. As another example, a gas source 136 (whichcould be provided by gas source 142 e) can periodically provide a pulseof inert gas, e.g., nitrogen, into the gas line 138 between the port 132and the vacuum source 130. The pulse of gas travels through the filter134 back toward the chamber 110 and can blow the particles off of thefilter 134. Isolation valves 139 a, 139 b can be used to ensure thatonly one of the gas source 136 or vacuum source 130 is fluidicallycoupled at a time to the line 138.

The chamber 110 is also coupled to a chemical delivery system 140. Thechemical delivery system 140 includes multiple fluid sources 142 coupledby respective delivery tubes 143, controllable valves 144, and a fluidsupply line 146. The chemical delivery system 140 delivers fluid to oneor more gas injection assemblies 190 that inject the fluid in a vaporform into the chamber 110. The chemical delivery system 140 can includea combination of restrictors, gas flow controllers, pressuretransducers, and ultrasonic flow meters to provide controllable flowrate of the various gasses into the chamber 110. The chemical deliverysystem 140 can also include one or more temperature control components,e.g., a heat exchanger, resistive heater, etc., to heat or cool thevarious gasses before they flow into the chamber 110.

The chemical delivery system 140 can include five fluid sources 142 a,142 b, 142 c, 142 d, 142 e. Two of the fluid sources, e.g., fluidsources 142 a, 142 b, can provide the two chemically differentprecursors or reactants for the deposition process for forming an oxidelayer on the particles. For example, the first fluid source 142 a canprovide trimethylaluminum (TMA) or titanium tetrachloride (TiCl4),whereas the second gas source 142 b can provide water. Another two ofthe fluid sources, e.g., fluid sources 142 c, 142 d, can provide the twochemically different precursors or reactants for the deposition processfor forming a polymer material on the oxide layer. For example, thethird fluid source 142 c can provide adipoyl chloride, and the fourthgas source 142 d can provide ethylene diamine. One of the fluid sources,e.g., the fifth fluid source 142 e, can provide an inert gas, e.g.,argon or N₂, for purging between cycles or half-cycles in the depositionprocess.

Although FIG. 1 illustrates five fluid sources, the use of fewer gassources could still be compatible with deposition of an oxide or polymerlayer, and use of more gas sources could enable formation of an evenwider variety of laminate structures.

For one or more of the fluid sources, the chemical delivery system 140delivers the precursor or reactant in liquid form to the gas injectionassembly 190. The gas injection assembly 190 includes a vaporizer 148 toconvert the liquid to vapor immediately before the precursor or reactantenters an injection manifold 194. This reduces upstream pressure loss toenable more pressure loss to occur across the particle bed 10. The morepressure loss that occurs across the particle bed 10, the lower theinjection apertures can be place, and the more likely that all of theprecursor will be reacted as it traverses the particle bed for a givenflow rate. The vaporizer 149 can be immediately adjacent the reactorside wall, e.g., secured to or housed within the reactor wall side 112.

As shown in FIG. 1 , there can be a manifold 194 for each precursor orreactant fluid, and each manifold 194 can be fluidically connectedseparately to the chamber 110. Thus, the precursors or reactants cannotmix until actually within the chamber 110. Alternatively, the gas linesfrom the fluid sources 142 could be joined as a combined fluid supplyline, e.g., by a valve. The gas injection assembly 190 will be discussedfurther below.

As noted above, a paddle assembly 150 is positioned in the chamber 110to agitate the particles in the particle bed. The paddle assembly 150includes a rotatable drive shaft 152 and a plurality of paddles 154. Thepaddles 154 are connected to the drive shaft 152 by struts 156 thatextend at outward from the drive shaft 152, such that rotation of thedrive shaft 152 about an axis of rotation 153 carries the paddles 154 ina circular path (see arrow C) around the axis of rotation 153. Thestruts 156 can extend perpendicular to the drive shaft 152. The driveshaft 152 and axis of rotation 153 can extend along the boundary betweenthe upper portion 110 b and the lower portion 110 a of the chamber 110.

The drive shaft 152 is driven by a motor 160 located outside the chamber110. For example, the drive shaft 152 can extend through the chamberwall 112 with one end coupled to the motor 160. A bearing vacuum seal162 can be used to seal the chamber 110 from the external environment.The other end of the drive shaft can be supported by a bearing insidethe chamber 110, e.g., the end of the drive shaft 152 can fit into arecess in the inner surface of the chamber wall 112. Alternatively, thedrive shaft 152 can simply be held in a cantilevered configuration withthe end of the drive shaft unsupported. This can be advantageous fordisassembly and cleaning. The motor 160 can rotate the drive shaft 152and paddle assembly 150 at speeds of 0.1 to 60 rpm.

At least some of the paddles 154 are held by the struts 156 in aposition such that, as the drive shaft 152 rotations, an outer edge of apaddle 154 almost contacts the interior surface 114 of the chamber wall112. However, the outer edge of the paddle 154 remains separated fromthe interior surface by a small gap G1, e.g., 1 to 4 mm. The gap G1 canbe as small as possible within manufacturing tolerances such that thepaddle 154 does not scrape the outer wall 112.

The axis of rotation 153 of the drive shaft 152 can be parallel, e.g.,collinear, with the center axis of the cylinder that defines the lowerportion 110 a. In this case, rotation of the drive shaft 152 can causethe outer edge of a paddle 154 to sweep across the half-cylinder innersurface, e.g., across the entirety of the half-cylinder inner surface,of the lower portion 110 a.

The paddles 154 can be spaced along the drive shaft 152 so as to ensurethat the paddles that almost contact the interior surface 114 providecoverage along substantially the entire length of the reactor chamber110. In particular, the paddles 154 be spaced and have a width W (alongthe axis of rotation) such that there are no gaps in the volume that isswept by the paddle assembly 150 s. In particular, the width W can begreater than the pitch of the paddles along the drive shaft 152. Thepaddles at the different axial positions along the length of the driveshaft can be angularly offset. For example, as shown in FIGS. 3A and 3B,the paddles 154 can be arranged in a spiral pattern around the driveshaft 152. However, many other configurations are possible for theangular offsets, e.g., alternating sides of the drive shaft.

In some implementations, some of paddles 154 are positioned radiallycloser to the drive shaft 152 than other paddles 154. The paddles 154 bthat are closer to the drive shaft can be termed “inner paddles,” andthe paddles 154 a that are farther from the drive shaft can be termed“outer paddles.” The inner and outer paddles 154 a, 154 b can either notbe overlapping radially, or can be partially overlapping radially. Forexample, the inner and outer paddles can overlap by at most 20% of theradial span S of the outer paddles (e.g., G≥0.8*S).

The outer paddles 154 a can be spaced and have a width (along the axisof rotation) such that there are no gaps in the volume being swept bythe outer paddles 154 a. In particular, the widths of the outer paddles154 a can be greater than the pitch of the outer paddles 154 a along thedrive shaft 152. Adjacent outer paddles 154 a along the length of thedrive shaft can be angularly offset. Similarly, the inner paddles 154 bcan also be spaced and have a width (along the axis of rotation) suchthat there are no gaps in the volume being swept by the inner paddles154 b. In particular, the widths of the inner paddles 154 b can begreater than the pitch of the inner paddles 154 b along the drive shaft152. Adjacent inner paddles 154 b along the length of the drive shaftcan be angularly offset. For example, as shown in FIGS. 3C and 3D, theinner paddles 154 b can be arranged in a first spiral around the driveshaft 152, and the outer paddles 154 a can be arranged in a secondspiral pattern around the drive shaft 152. The spirals of the inner andouter paddles 154 a, 154 b are shown as 180° out of phase, but this isnot required. Moreover, many other configurations are possible for theangular offsets between adjacent paddles, e.g., the paddles could beplaced on alternating sides of the drive shaft.

Referring to FIG. 4 , each paddle 154 can be a generally planar bodywith a primary surface 170 to push the particles in the particle bed,and a thinner edge 172 that will contact the inner surface of the lowerportion 110 a of the chamber 110. As shown in FIG. 4 , a paddle 154 canbe flared with a fan-shape. Or, as shown in FIGS. 1 and 2 , a paddle canbe generally rectangular, e.g., rectangular with rounded edges. Thesurface 170 of the paddle 154 can be flat, or the surface 170 could beconcave, e.g., spoon-shaped. In addition, in some implementations thepaddle 154 is plough-shaped, e.g., convex or sharply convex relative tothe direction of motion of the paddle.

Returning to FIG. 1 , in some implementations, paddles are clustered ingroups positioned in a common plane normal to the axis of rotation 153.The paddles in a group can be spaced at substantially equal angularintervals around the drive shaft 152. A group can include four paddles,although two, three or five or more paddles can be used.

For example, referring to FIGS. 1 and 5 , the paddle assembly 150includes a group 180 of four paddles 180 a, 180 b, 180 c, 180 d spacedat 90 degree angles apart and equidistant from the drive shaft 152 andaxis of rotation 153. The paddles 180 a-180 d can be positioned toalmost contact the half-cylinder inner surface of the lower portion 110a of the chamber 110 a.

As shown in FIGS. 1 and 2 , the paddle assembly 150 can include multiplegroups of paddles that are positioned at different locations along thedrive shaft 132. For example, the paddles assembly can include groups180, 182, 184, 186, 188. Where there are three or more groups, thegroups of paddles can be spaced at substantially equal intervals alongthe drive shaft 152. Each group can have the same number of paddles,e.g., four paddles. The paddles in adjacent groups can be offsetangularly about the axis of rotation, e.g., by half the angle betweenpaddles within a group. For example, if the groups have four paddlesspaced 90° apart about the axis of rotation, then paddles of adjacentgroups can be offset by 45°.

In some implementations, e.g., as shown in FIG. 1 , the paddles in agroup can be located substantially equal distances from the axis ofrotation 153, e.g., the struts 156 can have the same length.

However, in some implementations, some of the paddles in a group arepositioned radially closer to the drive shaft 152 than other paddles inthe group. For example, the paddle assembly 150 shown in FIG. 6Aincludes a group of four paddles 180 a′, 180 b′, 180 c′, 180 d′ spacedat 90 degree angles apart. Two of the paddles, e.g., two oppositepaddles 180 a′ and 180 c′, are located a first distance from the driveshaft 152. These two paddles can be positioned to nearly contact thehalf-cylindrical inner surface 112 of the lower portion 110 a. Anothertwo of the paddles, e.g., two opposite paddles 180 b′ and 180 d′, arelocated a shorter second distance from the drive shaft 152.

As another example, the paddle assembly shown in FIG. 6B includes agroup of eight paddles 180 a-180 h spaced at 45 degree angles apart.Four outer paddles 154 a, e.g., paddles 180 a-180 d, are located a firstdistance from the drive shaft 152. These four outer paddles 154 a can bepositioned to nearly contact the half-cylindrical inner surface 112 ofthe lower portion 110 a. Four inner paddles 154 b, e.g., paddles 180e-180 h, are located a shorter second distance from the drive shaft 152.The outer paddles 154 a and inner paddles 154 b are placed in analternating arrangement around the drive shaft 152.

In some implementations, some of the groups of paddles have paddles thatare positioned radially closer to the drive shaft 152 than the paddlesof other groups. For example, the paddle assembly 150 includes a group182 of four inner paddles 182 a, 182 b, 182 c, 182 d spaced at 90 degreeangles apart and equidistant from the drive shaft 152 and axis ofrotation 153. The outer edges of the paddles 182 a-182 d are spacedapart from the half-cylinder inner surface of the lower portion 110 a ofthe chamber 110 a by a gap G. The inner paddles 182 a-182 d are radiallyinward compared to the outer paddles 180 a-180 d.

Returning to FIGS. 1, 5 and 7 , each paddle 154 can be positioned andoriented such that an axis N normal to the planar face 170 of the paddle154 is perpendicular to the radius R passing from the axis of rotation153 to the paddle 154. However, in some implementations, one or morepaddles 154 can be angled such that orbiting of the paddle 154 about theaxis of rotation 153 tends to force the particles radially toward oraway from axis of rotation 153.

In addition, each paddle 154 can be at an oblique angle relative to theplane normal to the axis of rotation 153. In particular, each paddle 154can be angled such that orbiting of the paddle 154 about the axis ofrotation 153 tends to force the particles in a direction parallel to theaxis of rotation 153. For example, as shown in FIGS. 5 and 7 , a paddle180 a is oriented such that an axis N normal to the planar face 170 ofthe paddle 154 is at an oblique angle α relative to the axis of rotation153 when viewed along the radius (e.g., parallel to the strut 156)between the paddle 180 a and the axis of rotation 153. In thisconfiguration, when the paddle orbits about the axis of rotation 153, itwill have an instantaneous vector of motion C. The oblique angle α ofthe paddle 180 a will drive the powder in a direction D perpendicular tothe C. The oblique angle α can be between 15-75°, e.g., be between30-60°, e.g., be about 45°.

The inner paddles in a group can be oriented with a common oblique angleα, and the outer paddles in a group can be oriented with a commonoblique angle α′. In some implementations, all the inner paddles alongthe drive shaft 152 are oriented with a common oblique angle α, and allthe outer paddles along the drive shaft 152 are oriented with a commonoblique angle α′.

The angles α and α′ are not equal. In particular, the angles α and α′can have opposite sign. In some implementations, the angle α′ is ofequal magnitude but opposite sign as the angle α, e.g., the obliqueangle is +α for the outer paddles and −α for the outer paddles.

In some implementations, the outer paddles 154 are angled such thatorbiting of the paddles ends to force the particles in a first directionparallel to the axis of rotation 153, whereas the inner paddles 154 areangled such that orbiting of the inner paddles 154 tends to force theparticles in the anti-parallel direction, i.e., a second directionopposite the first direction. For example, referring to FIGS. 6 and 7 ,the outer paddles 180 a′ and 180 c′ in a group 180 can force theparticles in the direction D, whereas the inner paddles 180 b′ and 180d′ in the group can force the particles in a direction opposite to D.

Referring to FIG. 2 , in some implementations, a port 116 a is locatedsomewhere along, e.g., near the center of, the length of the chamber110. The port 116 a can be used to deliver and/or withdraw the particlesfrom the reactor 100. In such an implementation, the outer paddles canbe oriented to push the particles toward the port 116 a, and the innerpaddles can be oriented to push the particles away from the port 116 a.

For example, the outer paddles of groups 180 and 182 can push theparticles leftward toward the port 116 a, and the inner paddles ofgroups 180 and 182 can push the particles rightward away from the port116. Conversely, the outer paddles of groups 184, 186 and 188 can pushthe particles rightward toward the port 116 a, and the inner paddles ofgroups 184, 186 and 188 can push the particles leftward away from theport 116 a. Paddles oriented to push the particles a first direction,e.g., leftward, can be oriented with the oblique angle+α, whereaspaddles oriented to push the particles in an opposite second direction,e.g., rightward, can be oriented with the oblique angle −α.

If the paddles in each group have the same radial distance from thedrive shaft, the paddles in different groups, e.g., adjacent groups, canhave different oblique angles. For example, the paddles 180 a-180 d in afirst group 180 can force the particles in the direction D, whereaspaddles 182 a-182 d in a second group 180 can force the particles in adirection opposite to D (see FIG. 7 ).

Referring to FIGS. 1 and 8 , the chemical delivery system 140 is coupledto the chamber 110 by a gas injection assembly 190. The gas injectionassembly includes a plurality of apertures 192 that extend through thechamber wall 112. The apertures 192 can be arranged in a row, e.g.,parallel to the axis of rotation 153 of the drive shaft 152. AlthoughFIG. 8 illustrates a single row of apertures 192, the system can havemultiple rows of apertures. In particular, there can be different rowsof apertures for the different reactants or precursors. In addition,there can be multiples rows of apertures for a given reactant and/orprecursor.

The apertures 192 are located below the expected position of the topsurface 12 of the particle bed. In particular, the apertures 192 throughthe chamber wall 112 can be located in the lower portion 110 b of thechamber 110. For example, the apertures 192 can be extend through thecurved semicircular portion of the side wall 112. The apertures 192 canbe positioned in the lower half, e.g., the lower third, e.g., lowerquarter, e.g., lower fifth (as measured by vertically) of the chamberwall 112 of the lower portion 110 b. The apertures can have a diameterof 0.5 to 3 mm. Although FIG. 1 illustrates the apertures 192 areillustrated as extending through the chamber wall horizontally, this isnot required, as explained further below.

Referring to FIGS. 1 and 9 , the gas injection assembly 190 includes amanifold 194 with multiple channels 196 leading from the manifold 194 tothe apertures 192. The manifold 194 and channels 196 can be formed aspassages through a solid body 196 that provides a portion of the chamberwall 112. The vaporizer 148 can be positioned immediately upstream ofthe manifold 194.

An inert carrier gas, e.g., N₂, can flow from one of the fluid sources,e.g., the fluid source 142 e, through one or more passages 198 into themanifold 194. In operation, the carrier gas can flow continuously intothe manifold 194, i.e., whether or not the precursor or reactor gas isflowing into the manifold 194. As one example, the carrier gas can beinjected through a passage 198 a into the fluid line 146 before theliquid reaches the vaporizer. As another example, the carrier gas can beinjected through a passage 198 b directly into the vaporizer 148. Asanother example, the carrier gas can be injected through a passage 198 cdirectly into the manifold 194.

When the precursor or reactor gas is not being injected into the chamber110 through the manifold 194, the flow of the carrier gas can preventbackstreaming into the aperture 192 of the another precursor or reactorgas that is being injected from another manifold. The flow of carriergas can also prevent fouling of the aperture 192, e.g., blockage of theaperture, by the particles in the particle bed 10. In addition, thecarrier gas can provide the purge gas for the purge operation when theprecursor or reactor gas is not being injected into the chamber 110.

The flow of carrier gas into the vaporizer 149 when the precursor gas isalso flowing can improve vaporization of the precursor or reactantliquid. Without being limited by any particular theory, the carrier gasflow can assist in shearing the liquid during aerosolization, which canlead to smaller droplet size, which can be vaporized more quickly. Flowof the carrier gas into the manifold 148 when the precursor gas is alsoflowing can assist in drawing precursor gas out of the vaporizer.

Gas from the chemical delivery system 130, flows out of the apertures ina direction (indicated by arrow E) into the chamber 110. Assuming thatthe chamber 110 is partially filled with the particles, the gas isinjected near a bottom of the particle bed 10. Thus, the chemicals ofthe gas must “bubble” through the body of the particle bed 10 to escapeand be drawn out by the vacuum port 132. This can help ensure that theparticles are uniformly exposed to the gas.

The direction of rotation of the paddle assembly 150 (indicated by arrowC) can such that the paddle sweeps across the apertures 192 in adirection that has a component in the same direction (i.e., noanti-parallel component) as the gas flow (indicated by arrow E). Thiscan prevent the particles from being forced back against the gas flowand blocking the apertures 192.

Referring to FIG. 10 , the gas injection assembly 190 can be configuredto inject gas into the chamber 110 with a direction of gas flow that issubstantially parallel to the instantaneous direction of motion of thepaddle 154 as it passes over the apertures 192. Stated differently, thedirection of gas flow can be substantially tangent to the curved innersurface 114 of the cylindrical bottom portion 110 a of the chamber 110.

Each channel 196 can include a first channel portion 196 a that extendsat a shallow angle toward the inner surface 114. This first channelportion 196 a opens to the chamber 110 at apertures 192. As shown inFIG. 10 , the apertures 192 can be scalloped recesses with a sharpindent and then a depth that gradually decreases along the direction ofrotation (shown by arrow C) of the paddles 154. The first channelportion 196 a can open to a ceiling 192 a of the aperture 192 formed bythe sharp indent. This configuration can reduce likelihood of particlesfrom entering the channel 196. In addition, the first channel portion196 a can wider than the expected diameter of the particles. This canreduce the risk of particles clogging the first channel portion 196 a.

The channel 196 also includes a second channel portion 196 b thatextends between the manifold 194 and the first channel portion 196 a.The second channel portion 196 b is narrower than the first channelportion 196 a. This narrower channel portion 196 b controls flow rateand flow distribution out of the manifold 194.

The vaporizer 148 can include an internal cavity 148 a surrounded bywalls that are heated by a heater 148 b, e.g., a resistive heater,thermoelectric heater, heat lamp, etc. The fluid supply passage 146 iscoupled to the cavity 148 a by a nozzle 147. As the liquid passesthrough the nozzle 147, it is aerosolized. The combination of elevatedtemperature, rapid pressure change and high surface area of aerosolenables rapid vaporization of large quantities of the reactant orprecursor. The cavity 149 a of the vaporizer 148 can extend along asubstantial portion, e.g., at least half, of the length of the chamber110. The liquid reactant or precursor can be injected through the nozzle147 at one of the cavity, and an aperture 148 c for the reactant orprecursor vapor to pass into the manifold 194 can be located at oppositeend of the cavity chamber (along the length of the chamber 110).

As noted above, the vaporizer 148 can be integrated into the body thatprovides the manifold. For example, the vaporizer 148, manifold 194 andchannels 196 can all be part of a single unitary body.

In some implementations, one or more temperature control components areintegrated into the chamber walls 112 to permit control of thetemperature of the chamber 110. For example, resistive heater, athermoelectric cooler, a heat exchanger, or coolant flowing in coolingchannels in the chamber wall, or other component can be in or on theside walls 112.

The reactor system 10 also includes a controller 105 coupled to thevarious controllable components, e.g., the vacuum source 130, thechemical delivery system 140, the motor 160, the temperature controlsystem, etc., to control operation of the reactor system 100. Thecontroller 105 can also be coupled to various sensors, e.g., pressuresensors, flow meters, etc., to provide closed loop control of thepressure of the gasses in the chamber 110.

In general, the controller 105 is configured to operate the reactorsystem 100 in accord with a “recipe.” The recipe specifies an operatingvalue for each controllable element as a function of time. For example,the recipe can specify the times during which the vacuum source 130 isto operate, the times of and flow rate for each gas source 142 a-142 e,the rotation rate of the drive shaft 152 as set by the motor 160, etc.The controller 105 can receive the recipe as computer-readable data(e.g., that is stored on a non-transitory computer readable medium).

The controller 105 and other computing devices part of systems describedherein can be implemented in digital electronic circuitry, or incomputer software, firmware, or hardware. For example, the controllercan include a processor to execute a computer program as stored in acomputer program product, e.g., in a non-transitory machine readablestorage medium. Such a computer program (also known as a program,software, software application, or code) can be written in any form ofprogramming language, including compiled or interpreted languages, andit can be deployed in any form, including as a standalone program or asa module, component, subroutine, or other unit suitable for use in acomputing environment. In some implementations, the controller 105 is ageneral purpose programmable computer. In some implementations, thecontroller can be implemented using special purpose logic circuitry,e.g., an FPGA (field programmable gate array) or an ASIC (applicationspecific integrated circuit).

For a system of one or more computers to be configured to performparticular operations or actions means that the system has installed onit software, firmware, hardware, or a combination of them that inoperation cause the system to perform the operations or actions. For oneor more computer programs to be configured to perform particularoperations or actions means that the one or more programs includeinstructions that, when executed by data processing apparatus, cause theapparatus to perform the operations or actions.

Operation

Initially, particles are loaded into the chamber 110 in the reactorsystem 100. The particles can have a solid core comprising a drug, e.g.,one of the drugs discussed above. The solid core can optionally alsoinclude an excipient. Once any access ports are sealed, the controller105 operates the reactor system 100 according to the recipe in order toform the thin-film oxide layers and/or thin polymer layers on theparticles.

In operation, the reactor system 100 performs an ALD and/or an MLDthin-film coating process by introducing gaseous precursors of thecoating into the chamber 110. The gaseous precursors are spikedalternatively into the reactor chamber 110. This permits the depositionprocess to be a solvent-free process. The half-reactions of thedeposition process are self-limiting, which can provide Angstrom ornanometer level control of deposition. In addition, the ALD and/or MLDreaction can be performed at low temperature conditions, such as below50° C., e.g., below 35° C.

Suitable reactants for ALD methods include any of or a combination ofthe following: monomer vapor, metal-organics, metal halides, oxidants,such as ozone or water vapor, and polymer or nanoparticle aerosol (dryor wet). For example, the first fluid source 142 a can provide gaseoustrimethylaluminum (TMA) or titanium tetrachloride (TiCl4), whereas thesecond gas source 142 b can provide water. For MLD methods, as anexample, the fluid source 142 c can provide adipoyl chloride, and thefourth fluid source 142 d can provide vaporous or gaseous ethylenediamine.

In operation, one of the gasses flows from the chemical delivery system140 into the particle bed 10 in the lower portion 110 a of the chamber110 as the paddle assembly 150 rotates. Rotation of the paddle assembly150 agitates the particles to keep them separate, ensuring a largesurface area of the particles remains exposed. This permits fast,uniform interaction of the particle surface with the process gas.

For both an ALD process and an MLD process, two reactant gases arealternately supplied to the chamber 110, with each step of supplying areactant gas followed by a purge cycle in which the inert gas issupplied to the chamber 110 to force out the reactant gas andby-products used in the prior step.

As noted above, the coating process can be performed at low processingtemperature, e.g., below 50° C., e.g., at or below 35° C. In particular,the particles can remain or be maintained at such temperatures duringall of steps (i)-(ix) noted above. In general, the temperature of theinterior of the reactor chamber does not exceed 35° C. during of steps(i)-(ix). This can be achieved by having the first reactant gas, secondreactant gas and inert gas be injected into the chamber at suchtemperatures during the respective cycles. In addition, physicalcomponents of the chamber can remain or be maintained at suchtemperatures, e.g., using a cooling system, e.g., a thermoelectriccooler, if necessary.

In some implementations, the controller can cause the reactor system 100to first deposit an oxide layer on the drug-containing particles, andthen deposit a polymer layer over the oxide layer on the particles,e.g., using the process described above. In some implementations, thecontroller can cause the reactor system 100 alternate between depositingan oxide layer and depositing a polymer layer on the drug-containingparticles, so as to form a multi-layer structure with layers ofalternating composition.

Continuous Flow Operation

For an ALD process, the controller 105 can operate the reactor system100 as follows.

In a first reactant half-cycle, while the motor 160 rotates the paddlewheel 150 to agitate the particles:

-   -   i) The gas distribution system 140 is operated to flow the first        reactant gas, e.g., TMA, from the source 142 a into the chamber        110 until the particle bed 10 is saturated with the first        reactant gas. For example, the first reactant gas can flow at a        specified flow rate and for a specified period of time, or until        a sensor measures a specified first pressure or partial pressure        of the first reactant gas in the upper portion 110 b of the        chamber. In some implementations, the first reactant gas is        mixed with an inert gas as it flows into the chamber. The        specified pressure or partial pressure can be 0.1 Torr to half        of the saturation pressure of the reactant gas.    -   ii) Flow of the first reactant gas is halted, and the vacuum        source 140 evacuates the chamber 110, e.g., down to pressures        below 1 Torr, e.g., to 1 to 100 mTorr, e.g., 50 mTorr.

These steps (i)-(ii) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, in a first purge cycle, while the motor 160 rotates the paddlewheel 150 to agitate the particles:

-   -   iii) The gas distribution system 140 is operated to flow only        inert gas, e.g., N₂, from the source 142 e into the chamber 110.        The inert gas can flow at a specified flow rate and for a        specified period of time, or until a sensor measures a specified        second pressure of the inert gas in the upper portion 110 b of        the chamber. The second specified pressure can be 1 to 100 Torr.    -   iv) The vacuum pump 140 evacuates the chamber 110, e.g., down to        pressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (iii)-(iv) can be repeated a number of times set by therecipe, e.g., six to twenty times.

In a second reactant half-cycle, while the motor 160 rotates the paddleassembly 150 to agitate the particles:

-   -   v) The gas distribution system 30 is operated to flow the second        reactant gas, e.g., H₂O, from the source 142 b into the chamber        110 until the particle bed 10 is saturated with the second        reactant gas. Again, the second reactant gas can flow at a        specified flow rate and for a specified period of time, or until        a sensor measures a specified third pressure or partial pressure        of the second reactant gas in the upper portion 110 b of the        chamber. In some implementations, the second reactant gas is        mixed with an inert gas as it flows into the chamber. The third        pressure can be 0.1 Torr to half of the saturation pressure of        the second reactant gas.    -   vi) The vacuum pump 140 evacuates the chamber 110, e.g., down to        pressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (v)-(vi) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, a second purge cycle is performed. This second purge cycle withsteps (vii) and (vii) can be identical to the first purge cycle, or canhave a different number of repetitions of the steps (iii)-(iv) and/ordifferent specified pressure.

The cycle of the first reactant half-cycle, first purge cycle, secondreactant half cycle and second purge cycle can be repeated a number oftimes set by the recipe, e.g., one to ten times.

The operation is discussed above with an ALD process, but the operationis similar for MLD. In particular, in steps (i) and (v), the reactantgasses are substituted with appropriate process gasses and pressures fordeposition of a polymer layer. For example, step (i) can use vaporous orgaseous adipoyl chloride, and step (v) can use vaporous ethylenediamine.

Moreover, although operation is discussed above with an ALD or MLDprocess, the system could be used for a chemical vapor deposition (CVD)process. In this case, both reactants are flowed simultaneously into thechamber 110 so as to react inside the chamber, e.g., during step (i).The second reactant half-cycle can be omitted.

Pulsed Flow Operation

In another implementation, one or more of the gases (e.g., the reactantgases and/or the inert gas) can be supplied in pulses in which thechamber 110 is filled with the gas to a specified pressure, a delay timeis permitted to pass, and the chamber is evacuated by the vacuum source140 before the next pulse commences.

In particular, for an ALD process, the controller 105 can operate thereactor system 100 as follows.

In a first reactant half-cycle, while the motor 160 rotates the paddlewheel 150 to agitate the particles:

-   -   i) The gas distribution system 140 is operated to flow the first        reactant gas, e.g., TMA, from the source 142 a into the chamber        110 until a first specified pressure is achieved in the upper        portion 110 b of the chamber. The specified pressure can be 0.1        Torr to half of the saturation pressure of the reactant gas.    -   ii) Flow of the first reactant gas is halted, and a specified        delay time is permitted to pass, e.g., as measured by a timer in        the controller. This permits the first reactant to flow through        the particle bed 10 in the chamber 110 and react with the        surface of the particles.    -   iii) The vacuum pump 140 evacuates the chamber 110, e.g., down        to pressures below 1 Torr, e.g., to 1 to 100 mTorr, e.g., 50        mTorr.

These steps (i)-(iii) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, in a first purge cycle, while the motor 160 rotates the paddlewheel 150 to agitate the particles:

-   -   iv) The gas distribution system 140 is operated to flow the        inert gas, e.g., N₂, from the source 142 e into the chamber 110        until a second specified pressure is achieved. The second        specified pressure can be 1 to 100 Torr.    -   v) Flow of the inert gas is halted, and a specified delay time        is permitted to pass, e.g., as measured by the timer in the        controller. This permits the inert gas to diffuse through the        particles in the particle bed 10 to displace the reactant gas        and any vaporous by-products.    -   vi) The vacuum pump 140 evacuates the chamber 110, e.g., down to        pressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (iv)-(vi) can be repeated a number of times set by therecipe, e.g., six to twenty times.

In a second reactant half-cycle, while the motor 160 rotates the paddleassembly 150 to agitate the particles:

-   -   vii) The gas distribution system 30 is operated to flow the        second reactant gas, e.g., H₂O, from the source 142 b into the        chamber 110 until a third specified pressure is achieved. The        third pressure can be 0.1 Torr to half of the saturation        pressure of the reactant gas.    -   viii) Flow of the second reactant gas is halted, and a specified        delay time is permitted to pass, e.g., as measured by the timer        in the controller. This permits the second reactant gas to flow        through the particle bed 10 and react with the surface of the        particles inside the drum chamber 110.    -   ix) The vacuum pump 140 evacuates the chamber 110, e.g., down to        pressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr.

These steps (vii)-(ix) can be repeated a number of times set by therecipe, e.g., two to ten times.

Next, a second purge cycle is performed. This second purge cycle can beidentical to the first purge cycle, or can have a different number ofrepetitions of the steps (iv)-(vi) and/or different delay time and/ordifferent pressure.

The cycle of the first reactant half-cycle, first purge cycle, secondreactant half cycle and second purge cycle can be repeated a number oftimes set by the recipe, e.g., one to ten times.

Moreover, one or more of the gases (e.g., the reactant gases and/or theinert gas) can be supplied in pulses in which the chamber 110 is filledwith the gas to a specified pressure, a delay time is permitted to pass,and the chamber is evacuated by the vacuum source 140 before the nextpulse commences.

The operation is discussed above with an ALD process, but the operationis similar for MLD. In particular, in steps (i) and (vii), the reactantgasses are substituted with appropriate process gasses and pressures fordeposition of a polymer layer. For example, step (i) can use vaporous orgaseous adipoyl chloride, and step (vii) can use are vaporous ethylenediamine.

Moreover, although operation is discussed above with an ALD or MLDprocess, the system could be used for a chemical vapor deposition (CVD)process. In this case, both reactants are flowed simultaneously into thechamber 110 so as to react inside the chamber, e.g., during step (i).The second reactant half-cycle can be omitted.

CONCLUSION

The present disclosure provides apparatus for and methods of preparingpharmaceutical compositions comprising API containing particlesencapsulated by one or more layers of oxide and/or one or more layers ofa polymer. The coating layers are conformal and of controlled thicknessfrom several nanometers to several micrometers in total. The articles tobe coated can be composed of only API or a combination of API and one ormore excipients. The coating process described herein can provide an APIwith an increased glass transition temperature for the API relative touncoated API, a decreased rate of crystallization for an amorphous formof the API relative to uncoated API, and decreased surface mobility ofAPI molecules in the particle compared to uncoated API. Importantly,particle dissolution can be altered. Because the coating is relativelythin, drug products with high drug loading can be achieved. Finally,there are benefits with respect to cost and ease of manufacture becausemultiple coatings can be applied in the same reactor.

Terms of relative positioning are used to refer to relative positioningof components within the system or orientation of components duringoperation; it should be understood that the reactor system could be heldin a vertical orientation or some other orientation during shipping,assembly, etc.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.

What is claimed is:
 1. A method of coating particles, comprising:dispensing particles into a lower portion of a vacuum chamber, whereinthe lower portion of the vacuum chamber forms a half-cylinder having ahorizontally extending axial axis; evacuating the vacuum chamber througha vacuum port in an upper portion of the chamber; rotating a drive shaftsecured to a plurality of paddles such that the plurality of paddlesorbit the drive shaft and agitate the particles in the lower portion ofthe vacuum chamber, the plurality of paddles including plurality ofgroups of paddles positioned at different positions along the driveshaft with each group of paddles positioned in a common plane normal tothe drive shaft; and injecting a reactant or precursor gas into thelower portion of the chamber as the paddle assembly rotates.
 2. Themethod of claim 1, comprising coating the particles by atomic layerdeposition or molecular layer deposition.
 3. The method of claim 1,wherein the particles comprise a core containing a drug.
 4. The methodof claim 1, wherein each paddle of the plurality of groups of paddleshas a primary planar surface with a normal intersecting a plane normalto the horizontally extending axial axis at an oblique angle such thatrotating the drive shaft drives the powder in a direction parallel tothe drive shaft.
 5. The method of claim 4, wherein the plurality ofpaddles comprise a first plurality of outer paddles at a first radialdistance from the drive shaft and a first plurality of inner paddles ata second radial distance from the drive shaft, wherein the second radialdistance is smaller than the first radial distance.
 6. The method ofclaim 5, wherein the first plurality of outer paddles are oriented at afirst oblique angle so as to drive particles in a first direction alongthe axial axis and the second plurality of inner paddles are oriented ata second oblique angle that is opposite in sign to the first obliqueangle so as to drive particles in a second direction along the axialaxis opposite to the first direction.
 7. The method of claim 6, whereinthe second oblique angle is equal in magnitude to the first obliqueangle.
 8. The method of claim 6, wherein the plurality of paddlescomprise a second plurality of outer paddles at a third radial distancefrom the drive shaft and a second plurality of inner paddles at a fourthradial distance from the drive shaft, wherein the fourth radial distanceis smaller than the third radial distance, wherein the second pluralityof outer paddles are oriented at a third oblique angle so as to driveparticles in the second direction and the second plurality of innerpaddles are oriented at a fourth oblique angle so as to drive particlesin the first direction.
 9. The method of claim 8, wherein the thirdradial distance equals the first radial distance, the fourth radialdistance equals the second radial distance, and wherein the thirdoblique angle is equal in magnitude and opposite in direction to thefirst oblique angle, and the fourth oblique angle is equal in magnitudeand opposite in direction to the second oblique angle.
 10. The method ofclaim 9, wherein the third oblique angle equals the second oblique angleand the fourth oblique angle equals the first oblique angle.
 11. Themethod of claim 9, wherein the first plurality of outer paddles and thefirst plurality of inner paddles are positioned on a first side of adividing plane through the chamber normal to the axial axis, and thesecond plurality of outer paddles and the second plurality of innerpaddles are positioned on an opposite second side of the dividing plane.12. The method of claim 11, wherein rotation of the drive shaft causesthe outer paddles of the first plurality of outer paddles and secondplurality of outer paddles to push the particles toward the dividingplane and causes the inner paddles of the first plurality of innerpaddles and second plurality of inner paddles to push the particles awayfrom the dividing plane.
 13. The method of claim 11, wherein dispensingthe particles comprises delivering particles through a port into thevacuum chamber positioned at the dividing plane.
 15. The method of claim1, comprising sweeping along an entirety of a length of the chamberusing the plurality of paddles.
 16. The method of claim 1, comprisingmaintaining a gap between outer edges of the paddles and an innersurface of the lower portion of the chamber wall.
 17. The method ofclaim 16, wherein the gap is 1-3 mm.